The central role of insulin in human metabolism is to aid in the transport of glucose into muscle and fat cells. The disease states, such as diabetes mellitus, which result from defects in either the ability of the body to produce insulin or in defective insulin binding are well documented.
Type I or insulin dependent diabetes is characterized by decreased insulin production leading to hyperglycemia, ketoacidosis, thirst and weight loss. In general, defects in insulin production or activity are associated with hyperglycemia, i.e. the failure of cells to take up glucose and subsequent high circulating blood levels.
Epidemiological studies indicate that Type I diabetes, or non-insulin-dependent diabetes mellitus (NIDDM) can be characterized by high, normal or low insulin concentrations and insulin response to glucose. The Lancet, Jun. 17, 1989; p. 1356-1359. In general, NIDDM is associated with either insulin resistance or defective insulin secretion.
Recent studies have indicated a high correlation between defective glucose metabolism and relatives with NIDDM. Estimates are that 43 percent of first degree relatives of patients with NIDDM develop the disease. Raised fasting and glucose-stimulated insulin concentrations are early abnormalities in subjects destined to develop NIDDM. Even individuals with a family history of NIDDM who have normal blood glucose concentrations have higher insulin concentrations than individuals without a family history of NIDDM, indicating an increased insulin resistance despite the apparent lack of a disease state. Nagulesparan M. et. al. Diabetes (1979) 28: 980-83; Hollenbeck et. al. Diabetes (1984) 33:460-463; Lilloja et. al. Diabetes (1987) 36:1329-1335.
Many patients that show early signs of defective glucose metabolism experience disorders such a lack of concentration, depression and abnormal weight gain. Eriksson et. al. NEJM (1989) 321(6): 337-343. Apparently, the glucose receptor in the beta cell does not respond promptly, giving either a poor or delayed insulin response; and the insulin receptor in the muscle cell is slow to act and therefore the glucose does not get into the cell promptly. The result is hyperglycemia of varying intensity. Continued stimulation of the beta cell occurs, with gradually rising blood insulin levels until finally the insulin receptors respond, the blood glucose rushes into the cells and hypoglycemia results. Such hypoglycemia is generally referred to as reactive hypoglycemia.
Because this sequence of events occurs within 3 to 4 hours of a meal, the ensuing hypoglycemia remains undetected when a standard two hour test such as a glucose tolerance test, a two-hour euglycemic, hyperinsulinemic clamp and a hyperglycemicglucose clamp are utilized to measure glucose tolerance. Accordingly, the hyperglycemic state may be observed, while the following hypoglycemic reaction is not. Such studies indicate that relatives of patients with NIDDM had the same degree of disturbed glucose metabolism as patients diagnosed with the disease, creating a hyperglycemic state regardless of the relatively normal or high levels of circulating insulin. In each case, the level of glucose after two hours is higher than normal.
Oral diazoxide (7-chloro-3-methyl-2H-1,2,4-benzothiadiazine 1,1-diazoxide) is a drug originally developed for the treatment of hypertension. It is now used primarily for the treatment of hypoglycemia due to hyperinsulinism, associated with conditions such as inoperable islet cell adenoma or carcinoma. It is also used to suppress insulin in cases of nesidioblastosis in infants or, at times, in adenomas pre-operatively. It is currently marketed by prescription in the U.S. under the tradename Proglycem.RTM..
Diazoxide is known to cause hyperglycemia which is usually transitory (maximum 8 hours) and is due to decreased insulin secretion and decreased peripheral utilization of glucose. Henquin et. al. Diabetes 31:776-783 (1982). Despite the extensive amount of research dedicated to understanding glucose metabolism and the defects that result from defects in such metabolism, many persons suffer from hyperglycemic and hypoglycemic symptoms that remain undiagnosed. Of such undiagnosed illnesses, reactive hypoglycemia is a debilitating disease that often causes severe psychological problems.
It is the object of the present invention to provide a method of diagnosing and treating reactive hypoglycemia.
It is a further object of the invention to enhance the release of insulin and/or uptake of sugar in persons with disorders in glucose metabolism through the use of oral diazoxide.
It is a further object of the invention to provide a means of diagnosing Type II or pre-Type II diabetic conditions. It is a further object of the invention to prevent or delay the onset of insulin dependency in patients having pre-or early Type II diabetes.
It is a further object of the invention to provide a method of treating obesity caused by defective glucose metabolism through the use of oral diazoxide.
These as well as other objects of this invention are realized in light of the following disclosure.